Copper-catalyzed beta-Boration of alpha,beta-unsaturated carbonyl compounds: rate acceleration by alcohol additives

[reaction: see text] The efficient addition of bis(pinacolato)diboron to alpha,beta-unsaturated carbonyl compounds with a copper-diphosphine catalyst has been carried out. A dramatic rate acceleration of the reaction was realized by adding alcohol additives. With use of this procedure, a variety of alpha,beta-unsaturated carbonyl compounds including conjugated substrates at the acid oxidation level such as esters and nitriles were reacted to give to the corresponding beta-boryl carbonyl compounds in high yields.     

Ionic liquid as catalyst and reaction medium. The dramatic influence of a task-specific ionic liquid, [bmIm]OH, in Michael addition of active methylene compounds to conjugated ketones, carboxylic esters, and nitriles

[reaction: see text] A task-specific ionic liquid, [bmIm]OH, has been introduced as a catalyst and as a reaction medium in Michael addition. Very interestingly, although the addition to alpha,beta-unsaturated ketones proceeds in the usual way, giving the monoaddition products, this ionic liquid always drives the reaction of open-chain 1,3-dicarbonyl compounds with alpha,beta-unsaturated esters and nitriles toward bis-addition to produce exclusively bis-adducts in one stroke.     

Synthesis of Highly Functionalized gamma-Butyrolactones from Activated Carbonyl Compounds and Dimethyl Acetylenedicarboxylate

A triphenylphosphine-catalyzed cyclization of alpha-keto esters, alpha-keto nitriles, or alpha,alpha,alpha-trifluoroacetophenone with dimethyl acetylenedicarboxylate is reported to produce highly functionalized alpha,beta-unsaturated gamma-butyrolactones in moderate yields. Thus treating a mixture of methyl 4-nitrophenylglyoxylate and dimethyl acetylenedicarboxylate with 20 mol % of triphenylphosphine afforded 5,5'-disubstituted 3-methoxy-4-(methoxycarbonyl)-2(3H)-furanone in 94% yield. In the reaction of alpha-keto esters R(1)COCOOMe, an electron-withdrawing R(1) substituent is required for satisfactory reactivity. On the other hand, electron-donating R(1) substituents give higher yields with alpha-keto nitriles R(1)COCN. Another electron-deficient carbonyl compound, alpha,alpha,alpha-trifluoroacetophenone, gave the corresponding lactone in good yield. The use of an alpha-hydroxy ketone as an electrophilic carbonyl compound with more than 1 equiv of triphenylphosphine produced dihydrofuran derivatives. One equivalent of triphenylphosphine oxide was obtained as a major product. An intramolecular Wittig reaction is proposed as a reaction mechanism.     

Conjugate addition reactions of alpha-aminoalkylcuprates with alpha, beta-alkenyl-, alpha,beta-alkynyl-, alpha,beta-beta,gamma-allenyl-, and alpha,beta-gamma,delta-dienyl carboxylic acid derivatives, nitriles, and sulfoxides

alpha-Aminoalkylcuprates prepared from alpha-lithio carbamates and CuCN.2LiCl participate in 1,4-addition reactions with alpha, beta-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with alpha,beta-alkynyl esters, sulfoxides, and nitriles and with alpha,beta-beta,gamma-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of alpha-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.     

Diastereoselective and enantiospecific synthesis of gamma-substituted alpha,beta-unsaturated nitriles from O-protected allylic cyanohydrins

gamma-Functionalized alpha,beta-unsaturated nitriles are prepared diastereoselectively and enantiospecifically from enantioenriched cyanohydrin-O-phosphates and carbonates derived from alpha,beta-unsaturated aldehydes, either by palladium or iridium-catalyzed nucleophilic allylic substitution reactions with different nucleophiles. Appropriate reaction conditions for dibenzylamine, benzylamine, sodium azide, NaOAc, tetra-n-butylammonium acetate (TBAA), the corresponding sodium salts of phenol and N-hydroxysuccinimide and the carbonucleophile sodium dimethyl malonate are described. Different substituted O-protected cyanohydrins, such as carbonates and phosphates, derived from crotonaldehyde, (E)-hex-2-enal, oct-2-enal, 2-methylbut-2-enal, and cinnamaldehyde are used as allylic substrates. The substitution takes place with total retention of the configuration for the (E)-gamma-functionalized nitriles and with inversion of the configuration for the Z-isomers. In general, cyanohydrin-O-phosphates are the materials of choice to get the highest E-diastereoselectivity. Dibenzylamine is the best nucleophile for the synthesis of gamma-nitrogenated alpha,beta-unsaturated nitriles in the presence of either palladium or iridium catalysts when aliphatic compounds and cinnamaldehyde derivative are used (up to 98% dr). For the synthesis of gamma-oxygenated alpha,beta-unsaturated nitriles sodium or TBAA the reagents are selected to avoid epimerizations in up to 76% dr. Finally, the Tsuji-Trost reaction with sodium malonate works only under palladium catalysis in up to 70% dr.     

Efficient two-step conversion of alpha,beta-unsaturated aldehydes to optically active gamma-oxy-alpha,beta-unsaturated nitriles and its application to the total synthesis of (+)-patulolide C

[reaction: see text] An efficient two-step conversion of alpha,beta-unsaturated aldehydes into optically active gamma-oxy-alpha,beta-unsaturated nitriles is described. First, catalytic asymmetric cyanation-ethoxycarbonylation using (S)-YLi(3)tris(binaphthoxide) (YLB) afforded chiral allylic cyanohydrin carbonate. Second, a [3,3]-sigmatropic rearrangement proceeded without racemization under thermal conditions to give gamma-oxy-alpha,beta-unsaturated nitriles. Lewis acids were also effective for the rearrangement, and the reaction proceeded smoothly under mild conditions. To demonstrate the utility of the conversion, concise catalytic enantioselective total synthesis of (+)-patulolide C was performed.     

Synthesis of functionalized hydroquinones via [Cp*RuCl2]2-catalyzed cocyclization of alkynes, alpha,beta-unsaturated carbonyl compounds, and carbon monoxide

[reaction: see text] Catalytic [2 + 2 + 1 + 1] cocyclization reaction of an alkyne, an alkene, and two molecules of carbon monoxide, leading to functionalized hydroquinones, was studied. Using [Cp*RuCl2]2 as a catalyst, we found that a variety of electron-deficient alkenes, such as alpha,beta-unsaturated ketones, esters, amides, and nitriles, can be employed as an alkene coupling partner to give the corresponding hydroquinones.     

A facile and chemoselective conjugate reduction using polymethylhydrosiloxane (PMHS) and catalytic B(C6F5)3

A highly chemoselective conjugate reduction of electron-deficient Michael acceptors, including alpha,beta-unsaturated ketones, carboxylic esters, nitriles and nitro compounds with PMHS in the presence of catalytic B(C6F5)3 is described.     

Direct electrophilic diamination of functionalized alkenes without the use of any metal catalysts

A new direct electrophilic diamination reaction of alpha,beta-unsaturated ketones and esters has been established without the use of any metal catalysts. Three types of nitriles (CH(3)CN, CH(3)CH(2)CN, and CH(3)CH(2)CH(2)CN) were employed as nucleophilic nitrogen sources. A new mechanism has also been proposed to explain the resulting regio- and stereoselectivity.     

A novel chiral sulfonium yilde: highly enantioselective synthesis of vinylcyclopropanes

A newly designed chiral sulfonium allylide, generated in situ from the corresponding sulfonium salt in the presence of KOBu(t), reacted with alpha,beta-unsaturated esters, ketones, amides, and nitriles to afford trans-2-silylvinyl-trans-3-substituted cyclopropyl esters, ketones, amides, and nitriles with outstanding diastereoselectivity and excellent enantioselectivity in good to high yields. A mechanistic rationale is proposed.     

Preparation of fluoroalkyl imines, amines, enamines, ketones, alpha-amino carbonyls, and alpha-amino acids from primary enamine phosphonates

A simple method for preparation of fluoroalkyl beta-enaminophosphonates 1 from alkylphosphonates 2 and perfluoroalkyl nitriles 3 is reported. Olefination reaction of functionalized phosphates 1 with aldehydes gives alpha,beta-unsaturated imines 5. Acid hydrolysis of these fluoroalkyl derivatives 5 affords alpha,beta-unsaturated ketones 6, while their selective reduction with hydrides leads to the formation of allylamines 7, enamines 8, and saturated ketones 9 or amines 10. Selective oxidative cleavage of the carbon-carbon double bond of allylamines 7 gives fluorinated alpha-amino aldehydes 12, alpha-amino ketones 13, or alpha-amino acid derivatives 14.     

A tandem allylsilane-vinylsilane difunctionalization by silylcupration of allene followed by reaction with alpha,beta-unsaturated nitriles

Silylcupration of allene using phenyldimethylsilylcopper 1 followed by BF3-mediated reaction with alpha,beta-unsaturated nitriles at -40 degrees C affords allylsilane-vinylsilane-containing ketones resulting from consecutive addition (1,2 and 1,4) of the intermediate allyl- and vinylcopper species formed in the silylcupration of allene.     

Palladium-catalyzed cascade reaction of alpha,beta-unsaturated sulfones with aryl iodides

Unlike traditionally used acyclic 1,2-disubstituted alkenes, the reaction of alpha,beta-unsaturated phenyl sulfones with aryl iodides under Heck reaction conditions (Pd(OAc)(2) as catalyst, Ag(2)CO(3) as base in DMF at 120 (0)C) takes place mainly by a cascade process, involving one unit of the alkene and three units of the aryl iodide, to afford a substituted 9-phenylsulfonyl-9,10-dihydrophenanthrene. The dominant formation of this 3:1 coupling product, instead of the Heck trisubstituted olefin, shows that aromatic C-H bond activation processes can compete with the usually fast syn beta-hydrogen elimination step in the Heck arylation of an acyclic olefin. The structural scope of this palladium-catalyzed cascade arylation of alpha,beta-unsaturated sulfones has proved to be wide with regard to substitution at the beta-position (alkyl, aryl, or alkenyl substitution), substitution at the sulfone unit (alkyl or phenyl sulfones), and configuration at the CdoublebondC bond (trans or cis). Moreover, although less favored than in the case of the arylation of alpha,beta-unsaturated sulfones, similarly substituted 9,10-dihydrophenanthrenes have also been obtained in the case of alpha,beta-unsaturated phosphine oxides and alpha,beta-unsaturated phosphonate esters. A Pd(0)-Pd(II)-Pd(IV) mechanistic pathway involving the successive formation of highly electrophilic sigma-alkylpalladium intermediates and palladacycles is proposed for this multicomponent arylation.     

Fe(0)-mediated synthesis of tri- and tetra-substituted olefins from carbonyls: an environmentally friendly alternative to Cr(II)

Fe(0) was investigated as a cost-effective, environmentally friendly alternative to Cr(II) for the olefination of carbonyls by activated polyhalides. In many instances, Fe(0) was equivalent or superior to Cr(II). Notably, Fe(0), but not Cr(II), proved compatible with a wide range of functionality, inter alia, unprotected phenol, aryl nitro, carboxylic acid, and alkyl nitrile. A surprising reversal of stereoselectivity for aldehydes versus ketones was observed using both metals. The resultant alpha-halo-alpha,beta-unsaturated or alpha,beta-unsaturated carboxylic acids, esters, and nitriles are common structural elements in numerous compounds of interest as well as key intermediates in the preparation of other functionality.     

Extremely Efficient Chiral Induction in Conjugate Additions of p-Tolyl alpha-Lithio-beta-(trimethylsilyl)ethyl Sulfoxide and Subsequent Electrophilic Trapping Reactions

Reaction of p-tolyl alpha-lithio-beta-(trimethylsilyl)ethyl sulfoxide with alpha,beta-unsaturated esters gave the conjugate addition products as a single diastereomer. The intermediate enolates were subsequently trapped with various alkyl halides or aldehydes to give the products with extremely high stereoselectivity. The reaction with alpha,beta-unsaturated ketones also proceeded with high diastereoselectivity. Protolysis of the enolates derived from the alpha-methyl-alpha,beta-unsaturated esters gave the products with high stereoselectivity. The stereo- and regioselective elimination of the sulfinyl group gave chiral homoallylic carboxylates.     

Synthesis of functionalized carboranes as potential anticancer and BNCT agents

Carboranyl aldehydes react with alpha,beta-unsaturated esters, ketones, and nitriles in the presence of DABCO to provide functionalized carboranyl alcohols in good yields. Acetates of these alcohols undergo a facile isomerization with a variety of nucleophiles and afford structurally interesting carboranes. Biological evaluation of these molecules exhibited impressive antiproliferative activity for brain and breast cancer cells.     

Iron Carbonyl-Promoted Isomerization of Olefin Esters to Their alpha,beta-Unsaturated Esters: Methyl Oleate and Other Examples

Ultraviolet photolysis of stoichiometric amounts of methyl oleate and Fe(CO)(5) in hexanes solvent at 0 degrees C gives Fe(CO)(3)(eta(4)-alpha,beta-ester) in which the alpha,beta-unsaturated ester isomer of methyl oleate is stabilized by eta(4)-oxadiene pi coordination of the olefin and ester carbonyl groups to the Fe(CO)(3) unit. Treatment of the Fe(CO)(3)(eta(4)-alpha,beta-ester) with pyridine or CO liberates the free alpha,beta-ester, methyl octadec-trans-2-enoate, in 70% yield. The Fe(CO)(3) unit both catalyzes the olefin isomerization and stabilizes the alpha,beta-unsaturated ester, which results in the formation of the alpha,beta-ester in a yield far above that (3.5%) observed for simple catalyzed methyl oleate isomerization. The much smaller olefin esters, methyl 3-butenoate and ethyl 4-methyl-4-pentenoate, are isomerized under the same conditions to their alpha,beta-unsaturated esters in 94 and 90% yields, respectively. The effects of reaction conditions on the yield, the use of Fe(CO)(3)(cis-cyclooctene)(2) as a nonphotolytic catalyst, and the mechanism of this useful synthetic process are discussed.     

Formal [3 + 2] cycloadditions of donor-acceptor cyclopropanes and nitriles

Donor-acceptor cyclopropanes activated with Me3SiOTf cleave to reactive intermediates that can be efficiently intercepted by nitriles in a formal [3 + 2] dipolar cycloaddition reaction. Aliphatic, aromatic, and alpha,beta-unsaturated nitriles are excellent reaction partners, giving synthetically useful 2H-3,4-dihydropyrrole cycloaddition products in high yield.     

Umpolung of Michael acceptors catalyzed by N-heterocyclic carbenes

N-Heterocyclic carbenes can catalyze beta-alkylations of a range of alpha,beta-unsaturated esters, amides, and nitriles that bear pendant leaving groups to form a variety of ring sizes. In this process, the nucleophilic catalyst transiently transforms the normally electrophilic beta carbon into a nucleophilic site through an unanticipated addition-tautomerization sequence.     

Fluoroalkyl alpha,beta-unsaturated imines. Valuable synthetic intermediates from primary fluorinated enamine phosphonates

[reaction: see text] A simple method for the preparation of fluoroalkyl allylamines or alpha,beta-unsaturated ketones by an olefination reaction of primary enamine phosphonates and aldehydes, followed by selective reduction with hydrides or hydrolysis, is reported. Fluorinated beta-amino nitriles are also obtained by an olefination reaction of primary enamine phosphonates with aldehydes and subsequent addition of metalated acetonitrile.